Amine derivatives

ABSTRACT

The invention provides compounds of general formula ##STR1## and physiologically acceptable salts, hydrates and bioprecursors thereof, in which 
     Y and Z, which may be the same or different, each represent oxygen, sulphur, =CHNO 2  or =NR 3  where R 3  is hydrogen, nitro, cyano, lower alkyl, aryl, alkylsulphonyl or arylsulphonyl; 
     p has a value from 2 to 12; 
     R 1  represents ##STR2## in which R 4  and R 5  which may be the same or different, each represent hydrogen, lower alkyl, cycloalkyl, lower alkenyl, aralkyl or lower alkyl interrupted by an oxygen atom or a group &gt;N-R 6  in which R 6  represents hydrogen or lower alkyl, or R 4  and R 5  together with the nitrogen atom to which they are attached form a 5 to 7-membered saturated heterocyclic ring which may contain an additional oxygen atom or the group &gt;NR 6  ; 
     Q represents a furan or thiophen ring in which incorporation into the rest of the molecule is through bonds at the 2 and 5 positions, or a benzene ring in which incorporation into the rest of the molecule is through bonds at the 1 and 3 or 1 and 4 positions; 
     X represents --CH 2  --, --O-- or --S--; 
     n represents zero or 1; 
     m represents 2, 3 or 4 and 
     Alk represents a straight chain alkylenegroup of 1 to 3 carbon atoms; 
     and R 2  represents lower alkyl or the group 
     
         --(CH.sub.2).sub.y E(CH.sub.2).sub.x G 
    
     in which 
     Y represents 2, 3 or 4 or can additionally 
     represent zero or 1 when E is a --CH 2  -- group; 
     x represents zero, 1 or 2; 
     E represents --CH 2  --, --0-- or --S--; and 
     G represents a monocyclic 5 or 6 membered carbocyclic or heterocyclic aromatic ring, or G represents the group ##STR3## where Q&#39; represents any of the rings defined for Q; 
     Alk&#39; represents any of the groups defined for Alk; 
     and R 4  &#39; and R 5  &#39; which may be the same or different represent any of the groups defined for R 4  or R 5 . 
     The compounds of formula (I) have pharmacological activity as selective histamine H 2  -antagonists.

This invention relates to novel α,ω-disubstituted polymethylenecompounds having action on histamine receptors, to processes for thepreparation thereof, to pharmaceutical compositions containing them andto their use in therapeutics.

Certain novel α,ω-disubstituted polymethylene compounds have now beenfound which have potent activity as H₂ -antagonists. These compounds,which are more particularly described below, for example show inhibitionof the secretion of gastric acid when this is stimulated via histaminereceptors (Ash and Schild, Brit. J. Pharmacol. Chemother, 1966, 27,427). Their ability to do so can be demonstrated in the perfused ratstomach using the method described in German Offenlegungsschrift No.2,734,070, modified by the use of sodium pentobarbitone (50 mg/kg) asanaesthetic instead of urethane, and in conscious dogs equipped withHeidenhain pouches using the method described by Black et al, Nature1972, 236, 385. Furthermore the compounds antagonise the effect ofhistamine on the contraction frequency of isolated guinea pig rightatrium but do not modify histamine induced contractions of isolatedgastro-intestinal smooth muscle which are mediated via H₁ -receptors.

Compounds with histamine H₂ -blocking activity may be used in thetreatment of conditions where there is a hypersecretion of gastric acid,particularly in gastric and peptic ulceration, as a prophylactic measurein surgical procedures, and in the treatment of allergic andinflammatory conditions where histamine is a known mediator. Thus theymay be used for example, either alone, or in combination with otheractive ingredients in the treatment of allergic and inflammatoryconditions of the skin.

The present invention provides compounds of general formula (I) ##STR4##and physiologically acceptable salts, hydrates and bioprecursorsthereof, in which

Y and Z, which may be the same or different, each represent oxygen,sulphur, ═CHNO₂ or ═NR₃ where R₃ is hydrogen, nitro, cyano, lower alkyl,aryl, alkylsulphonyl or arylsulphonyl;

p has a value from 2 to 12;

R₁ represents ##STR5## in which R₄ and R₅ which may be the same ordifferent, each represent hydrogen, lower alkyl, cycloalkyl, loweralkenyl, aralkyl or lower alkyl interrupted by an oxygen atom of a group>N--R₆ in which R₆ represents hydrogen or lower alkyl, or R₄ and R₅together with the nitrogen atom to which they are attached form a 5 to7-membered saturated heterocyclic ring which may contain an additionaloxygen atom or the group >NR₆ ;

Q represents a furan or thiophen ring in which incorporation into therest of the molecule is through bonds at the 2 and 5 positions, or abenzene ring in which incorporation into the rest of the molecule isthrough bonds at the 1 and 3 or 1 and 4 positions;

X represents --CH₂ --, --O-- or --S--;

n represents zero or 1;

m represents 2, 3 or 4 and

Alk represents a straight chain alkylene group of 1 to 3 carbon atoms;

and R₂ represents lower alkyl or the group

    --(CH.sub.2).sub.y E(CH.sub.2).sub.x G

in which

y represents 2, 3, or 4 or can additionally represent zero or 1 when Eis a --CH₂ -- group;

x represents zero, 1 or 2;

E represents --CH₂ --, --O-- or --S--; and

G represents a monocyclic or 5 or 6 membered carbocyclic or heterocyclicaromatic ring, or G represents the group ##STR6## where Q' representsany of the rings defined for Q;

Alk' represents any of the groups defined for Alk;

and R₄ ' and R₅ ' which may be the same or different represent any ofthe groups defined for R₄ and R₅.

Preferably when Q, Q' or G is a furan ring then x and n are not zerowhen X or E is oxygen.

The term `lower` as applied to `alkyl` means that the group has 1 to 6carbon atoms, and in particular 1 to 4 carbon atoms, and when applied to`alkenyl` that the group has 3 to 6 carbon atoms. The term `aryl` as agroup or part of a group preferably means phenyl or substituted phenyl,for example phenyl substituted with one or more alkyl, alkoxy or halogengroups. The monocyclic 5 or 6 membered carbocyclic or heterocyclicaromatic ring is preferably benzene, furan or thiophen.

According to one preferred aspect the invention provides compounds offormula (I) in which R₁ and R₂ may be the same or different and R₁represents ##STR7## where R₄, R₅, Alk, Q, n, X and m are as defined informula (I) and R₂ represents ##STR8## where R₄ ', R₅ ', Alk', Q', X andE are as defined in formula (I) and y is 2, 3 or 4, with the provisothat n is not zero when X is oxygen and Q is a furan or thiophen ringsystem and x is not zero when E is oxygen and Q' is a furan or thiophenring system.

Preferably R₂ represents ##STR9## where R₄ ', R₅ ', Alk', Q', x and Eare as defined in formula (I) and y is 2, 3 or 4 or R₂ represents analkyl group, most preferably methyl. Preferably R₄, R₅, R₄ ' and R₅ 'are alkyl groups, most preferably methyl. Preferably Alk or Alk' is CH₂.Preferably m and y are 2 or 3. Preferably p is 3, 4 or 12. Preferably Yand Z are ═CHNO₂ or ═S and they are preferably the same. When Q or Q' isfuran preferably n or X or E is sulphur and m or y is 2. In this casepreferably Y and Z are ═CHNO₂ and p is 3 or 12. When Q or Q' is1,3-benzene preferably n is x is zero, X or E is oxygen and m or y is 3.In this case preferably Y and Z are ═CHNO₂ or ═S and p is 3 or 4.

Particularly preferred compounds areN,N'-bis[1-[[2-[[5-[(dimethylamino)methyl]-2-furanyl-methyl]thio]ethyl]amino]-2-nitroethenyl]-1,3-propanediamine.

N,N'-bis[1-[[2-[[5-[(dimethylamino)methyl]-2-furanylmethyl]thio]ethyl]amino]-2-nitroethenyl]-1,12-dodecanediamine

N,N'-bis[1-[[3-[3-[dimethylamino)methyl]phenoxy]propyl]amino]-2-nitroethenyl]-1,4-butanediamine

N-[2-[[5-[(dimethylamino)methyl]-2-furanylmethyl]thio]-ethyl]-N'-[12-[[1-(methylamino)-2-nitroethenyl]amino]dodecyl]-2-nitro-1,1-ethene-diamine

N,N"-1,3-propanediylbis-[N'-[3-[3-(dimethylamino)methyl]phenoxy]propyl]thiourea].

The invention includes the compounds of formula (I) in the form ofphysiologically acceptable salts with inorganic and organic acids.Particularly useful salts include hydrochlorides, hydrobromides andsulphates; acetates, maleates, succinates, citrates and fumarates. Thecompounds of formula (I) and their salts may also form hydrates, whichhydrates are also to be considered as part of the invention. Thecompounds of formula (I) can exhibit tautomerism and the formula isintended to cover all tautomers. Where optical isomers may exist theformula is intended to cover all diastereoisomers and opticalenantiomers.

The compounds according to the invention, preferably in the form of asalt, may be formulated for administration in any convenient way and theinvention includes within its scope pharmaceutical compositionscontaining at least one compound according to the invention adapted foruse in human or veterinary medicine. Such compositions may be formulatedin a conventional manner using one or more pharmaceutically acceptablecarriers or excipients. Such compositions may also contain if requiredother active ingredients, e.g. H₁ -antagonists.

Thus the compounds according to the invention may be formulated fororal, buccal, topical, parenteral or rectal administration. Parenteraladministration is preferred.

For oral administration, the pharmaceutical composition may take theform of for example, tablets, capsules, powders, solutions, syrups orsuspensions prepared by conventional means with acceptable excipients.For buccal administration the composition may take the form of tabletsor lozenges formulated in conventional manner.

The compounds of the invention may be formulated for parenteraladministration by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form in ampoules, or inmulti-dose containers, with an added preservative. The compositions maytake such forms as suspensions solutions or emulsions in oily or aqueousvehicles, and may contain formulatory agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form for reconstitution with a suitablevehicle, e.g. sterile pyrogen-free water before use.

The compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g. containingconventional suppository bases such as cocoa butter or other glyceride.

For topical application, the compounds of the invention may beformulated as ointments, creams, gels, lotions, powders or sprays.Ointments and creams may for example, be formulated with an aqueous oroily base with the addition of suitable pharmaceutical excipients.Lotions may be formulated with an aqueous or oily base and will includethe necessary adjustments to ensure pharmaceutically acceptableproducts. Spray compositions may, for example, be formulated as aerosolswhich may be pressurised by means of a suitable agent such asdichlorofluoromethane or trichlorofluoromethane or may be delivered bymeans of a hand-operated atomizer.

For internal administration a convenient daily dosage regime of thecompounds according to the invention would be 2 to 4 doses to the totalof some 200 mg to 2 g per day.

As will be appreciated by those skilled in the art, in the steps thatfollow it may be necessary to protect certain reactive substituents inthe starting materials for a particular reaction and subsequently toremove the protecting group after completion of the reaction. Suchprotection and subsequent deprotection is especially pertinent when R₄and/or R₅ or R₄ ' and/or R₅ ' are hydrogen in the grouping ##STR10##within the groups R₁ and/or R₂. Standard protection procedures may beemployed e.g. formation of phthalimide (in the case of primary amines),N-benzyl, N-benzyloxycarbonyl, or N-trichloroethyloxycarbonylderivatives. Subsequent cleavage of the protecting group is achieved byconventional procedures. Thus a phthalimide group may be cleaved bytreatment with a hydrazine, e.g. hydrazine hydrate, or a primary amine,e.g. methylamine, N-benzyl or N-benzyloxycarbonyl derivatives may becleaved by hydrogenolysis in the presence of a catalyst, e.g. palladium,and N-trichloroethyloxycarbonyl derivatives may be treated with zincdust.

Compounds of formula (I) may be prepared by reacting an amine (II)

    VNH.sub.2                                                  (II)

with a reagent (III)

    WNAB                                                       (III)

in which either

V represents the grouping ##STR11## and W represents R₁ or R₂ or

V represents R₁ or R₂ and

W represents the grouping ##STR12## in which R₁, R₂, Y, Z and p are asdefined in formula (I). and A represents hydrogen and B represents##STR13## where L is a leaving group such as thiomethyl and Y and Z eachrepresent ═CHNO₂ or ═NR₃ or

A and B together represent ═C═Y or ═C═Z

where Y and Z each represent ═O or ═S, and R₃ is as defined in formula(I).

Embodiments of the above process are as follows:

Compounds of formula (I) in which R₁ is the same as R₂, Y is the same asZ and Y is ═NR₃, or ═CHNO₂ may be made by heating a diameter of formula(IV)

    H.sub.2 N(CH.sub.2).sub.p NH.sub.2                         (IV)

in which p is as defined above, with two molecular equivalents of acompound of formula (V) ##STR14## in which R₁ is as defined in formula(I), Y is ═CHNO₂ or ═NR₃ where R₃ is as defined in formula (I) and L isa leaving group such as thioalkyl, e.g. thiomethyl or alkoxy, e.g.ethoxy; preferably thiomethyl.

Compounds of formula (I) in which R₁ is the same as R₂, Y is the same asZ and Y is oxygen or sulphur may be made by reacting the diamine (IV)with two molecular equivalents of an isocyanate or isothiocyanate forformula (VI)

    R.sub.1 N═C═Y                                      (VI)

in which R₁ is as defined in formula (I) and Y is oxygen or sulphur,preferably in a solvent such as acetonitrile. An isocyanate of formula(VI) may be prepared by treating an amine of formula (VII)

    R.sub.1 NH.sub.2                                           (VII)

with phosgene and a base preferably triethylamine. An isothiocyanate offormula (VI) may be prepared by treating the amine (VII) as definedabove with carbon disulphide followed by reaction with a chloroformateester e.g. ethyl chloroformate or with decomposition of the intermediateformed with carbon disulphide using mercuric chloride and a base e.g.triethylamine.

Compounds of formula (I) in which R₁ differs from R₂ and/or Y differsfrom Z and may be prepared by two-stage processes.

In order to prepare compounds of formula (I) in which R₁ is the same asR₂, Y differs from Z, and in which Y is ═CHNO₂ or ═NR₃ where R₃ is asdefined in formula (I) a diamine of formula (IV) can be reacted with onemolecular equivalent of a compound of formula (V) where R₁ and L are asdefined and Y is ═CHNO₂ or ═NR₃ to produce an intermediate of formula(VIII) ##STR15## in which Y represents ═CHNO₂ or ═NR₃ which can then bereacted with one molecular equivalent of a compound of formula (IX)##STR16## in which L is a leaving group as defined above and Z differsfrom Y, the reaction being carried out in the absence or presence of asolvent e.g. water, dioxan, ethyl acetate or acetonitrile, at roomtemperature or above.

Alternatively, the intermediate of formula (VIII) could subsequently bereacted with a compound of formula (X)

    R.sub.1 N═C═Z                                      (X)

in which R₁ is as defined in formula (I) and Z is oxygen or sulphur,preferably in a solvent such as acetonitrile to give compounds offormula (I) in which R₁ is the same as R₂, Y differs from Z and Y is═CHNO₂ or ═NR₃ and Z is O or S.

Similarly in order to prepare compounds of formula (I) in which R₁differs from R₂, Y may or may not differ from Z and Y is ═CHNO₂ or ═NR₃where R₃ is as defined in formula (I), an intermediate of formula (VIII)in which R₁ is as defined and Y is ═CHNO₂ or ═NR₃ may be reacted withone molecular equivalent of a compound of formula (XI) or (XII)respectively ##STR17##

Alternatively the reaction may be carried out with compounds of formula(VIII), (XI) and (XII) in which R₁ is replaced by R₂ and R₂ is replacedby R₁.

Compounds of formulae (IX), (XI) and (XII) in which Y and Z are ═CHNO₂or ═NR₃ may be prepared by reacting the appropriate amine of formula(VII) or (XIII)

    R.sub.2 NH.sub.2                                           (XIII)

with a compound of formula (XIV) or (XV) ##STR18## where R₃ and L are asdefined in formula (III) and L' is as for L but may also be a group##STR19## where R₆ represents an alkyl group, the reaction being carriedout in a solvent such as ether, acetonitrile, dioxan or ethyl acetate,at a temperature from ambient to reflux.

Compounds of formulae (IX), (XI) and (XII) in which Y and Z are oxygenor sulphur may be prepared from amines of formulae (VII) or (XIII) byconventional means, for example using phosgene or carbon disulphidefollowed by dimethylsulphate.

To prepare compounds of formula (I) in which R₁ is the same as R₂, Y isthe same as Z and Y is sulphur, the amine of formula (IV) may beconverted into a diisothiocyanate of formula (XVI)

    Y═C═N(CH.sub.2).sub.p N═C═Y                (XVI)

where Y represents sulphur, by means described above for the preparationof isothiocyanates. The compound of formula (XVI) may then be reactedwith two molecular equivalents of an amine of formula (VII) to give acompound of formula (I) in which Y is sulphur, R₁ is the same as R₂ andY is the same as Z. Similarly, compounds of formula (I) in which Y isoxygen, R₁ is the same as R₂ and Y is the same as Z may be prepared fromcompounds of formula (IV) by reaction with phosgene and a base, forexample triethylamine, to give an intermediate of formula (XVI) in whichY represents oxygen, followed by reaction with two molecular equivalentsof the amine (VII).

Compounds of formula (I) in which R₁ differs from R₂ and/or Y differsfrom Z, and in which Y and Z are oxygen or sulphur may be prepared froman intermediate of formula (VIII) in which Y is oxygen or sulphur. Thisintermediate may be made by reacting an isocyanate or isothiocyanate offormula (VI) with excess of the diamine (IV). The compound of formula(VIII) in which Y is oxygen or sulphur is then reacted with theappropriate compound of formula (VI) i.e. R₁ N═C═Z, R₂ N═C═Y or R₂N═C═Z.

In an alternative process to compounds of formula (I) in which R₁ is thesame as R₂ an intermediate of formula (XVII) ##STR20## in which Y, Z, pand L are as defined in formulae (I) and (III), may be reacted with twomolecular equivalents of an amine of formula (VII). The reaction may becarried out in a solvent, e.g. acetonitrile at elevated temperature, or,where Y and Z are ═CHNO₂ in aqueous solution at room temperature.

The compounds of formula (XVII) in which p is preferably greater than 3,and Y and Z are the same and are ═CHNO₂ or ═NR₃ may be prepared byreacting an excess of a compound of formula (XIV) or (XV) with thediamine (IV). Compounds of formula (XVII) in which Y and Z are differentand are ═CHNO₂ or ═NR₃ may be made by reacting an excess of the diamine(IV) with a compound of formula (XIV) with subsequent reaction of theintermediate so formed with a compound of formula (XV) or vice versa.

Compounds of formula (I) can also be prepared by reacting an amine offormula (VII) with a compound capable of converting the amino group intoa group ##STR21## in which Y, Z, R₂ and p are as defined in formula (I).Compounds which are capable of this conversion are isocyanates,isothiocyanates or compounds of formula (XVIII) where Y represents ═NR₃or ═CHNO₂ and L is a leaving group as defined above. The isocyanates andisothiocyanates will be of formula (XIX) ##STR22## in which p is greaterthan 3, Y is oxygen or sulphur, and the reaction may be carried out byallowing the amine (VII) and isocyanate or isothiocyanate to react in asolvent such as acetonitrile. The reaction between the amine (VII) and acompound of formula (XVIII) where Y represents ═CHNO₂ may be carried outby stirring the reactants in aqueous solution at room temperature. Thereaction between the amine (VII) and a compound of formula (XVIII) mayalso be carried out by heating the reactants in the absence or presenceof a solvent, e.g. acetonitrile, at a temperature of, for example 100°to 120° C.

Further processes for preparing the compounds of formula (I) are asfollows:

Compounds of formula (I) in which, in R₁, n is 1, X is sulphur and othergroups are as defined in formula (I) may be prepared from compounds offormulae ##STR23## where R₄, R₅ and Q are as defined in formula (I) andD represents a leaving group such as halogen e.g. bromine or an acyloxygroup e.g. acetoxy, using a thiol of formula (XXII) ##STR24##

The reaction between a thiol (XXII) and a compound of formula (XX) ispreferably carried out in the presence of a strong base e.g. sodiumhydride at room temperature in an organic solvent e.g.dimethylformamide. The reaction between a thiol (XXII) and a compound offormula (XXI) is preferably carried out at 0° C. in a mineral acid e.g.concentrated hydrochloric acid. The starting materials of formula (XX)may be prepared from alcohols of formula (XXI) by conventional means.

Compounds of formula (I) in which, in at least one of R₁ and R₂, Q or Q'is a furan ring and Alk or Alk' is methylene and Y and Z are other than═CHNO₂, can be prepared from compounds of formula (XXIII) ##STR25## by aMannich reaction using formaldehyde and a secondary amine or a salt of aprimary or secondary amine. The process may be carried out by reactingthe amine salt with aqueous formaldehyde and the compound of formula(XXIII) or by refluxing the amine salt with paraformaldehyde in asuitable solvent, e.g. ethanol, with the compound of formula (XXIII).When G represents an unsubstituted furan ring the Mannich reaction canalso take place at this ring.

Compounds of formula (I) in which, in at least one of R₁ and R₂, R₄ andR₅ or R₄ ' and R₅ ' are both methyl, Alk or Alk' is CH₂, and Q or Q' isfuran or thiophen and Y and Z are other than ═CHNO₂, can be prepared bytreating a compound of formula (XXIV) ##STR26## where U representsoxygen or sulphur and Y and Z are other than ═CHNO₂, with a reagent offormula (XXV)

    (CH.sub.3).sub.2 N.sup.⊕ =CH.sub.2 Cl.sup.⊖    (XXV)

in a solvent e.g. acetonitrile at reflux temperature.

When G represents an unsubstituted thiophen or furan ring the group(CH₃)₂ N CH₂ may also be added to this ring.

When the groups R₄ and R₅ or R₄ ' and R₅ ' in compounds of formula (I)are hydrogen they may be converted where appropriate into alkyl oraralkyl groups using, for example, an alkyl or aralkyl halide.

Amines of formulae (VII) and (XIII) may be prepared as described inGerman Offenlegungsschrifts Nos. 2734070, 2821410 and 2821409 or bymethods analagous to those described in these documents.

Where the product of any of the above processes is a free base and asalt is required, the salt may be formed in a conventional manner. Thus,for example, a generally convenient method of forming the salts is tomix appropriate quantities of the free base and the acid in anappropriate solvent(s), e.g. an alcohol such as ethanol or an ester suchas ethyl acetate.

The invention is illustrated but not limited by the following Examples.In these examples the TLC data was obtained using silica plates"Polygram" SIL G/UV 254 0.25 mm thick.

EXAMPLE I

(i)N,N'-Bis-[1-[[2-[[5-[(dimethylamino)methyl]-2-furanylmethyl]thio]ethyl]amino]-2-nitroethenyl]-1,12-dodecanediamine.

A mixture ofN,N-dimethyl-5-[[[2-[(1-methylthio-2-nitroethenyl)amino]ethyl]thio]methyl]-2-furanmethanamine(2 g) and 1,12-diaminododecane (0.6 g) was heated at 100° for 3 hours.The oily residue was chromatographed (silica/methanol-0.88 ammonia,79:1) to give an oil which solidified on trituration with ether givingthe title compound (1.77 g) mp. 74°-76°.

Found: C,55.9; H,7.8; N,14.5; C₃₆ H₆₂ N₈ O₆ S₂ Requires: C,56.4; H,8.1;N,14.6%.

Similarly prepared were:

(ii)N,N'-Bis-[1-[[2-[[5-[(dimethylamino)methyl]-2-furanylmethyl]thio]ethyl]amino]-2-nitroethenyl]-1,10-decanediaminesulphate (0.68 g) as an oil fromN,N-dimethyl-5-[[[2-[(1-methylthio-2-nitroethenyl)amino]ethyl]thio]methyl]-2-furanmethanamine oxalate (1.5 g) and1,10-diaminodecane (0.25 g) in 8% aqueous bicarbonate (10 ml) at roomtemperature for 2 hours and 98°-100° for 4 hours followed by columnchromatography (silica/methanol-0.88 ammonia, 79:1) and evaporation ofeluates in the presence of ammonium sulphate.

TLC. (silica/methanol-0.88 ammonia, 79:1) Rf 0.37

Found: C,51.6; H,7.8; N,13.9; C₃₄ H₅₈ N₈ O₆ S₂.1/2H₂ SO₄ Requires:C,51.8; H,7.6; N,14.2%.

(iii)N,N'-Bis-[1-[[2-[[5-[(dimethylamino)methyl]-2-furanylmethyl]thio]ethyl]amino]-2-nitroethenyl]1,3-propanediamine(0.47 g), mp. 141°-145°, fromN,N-dimethyl-5-[[[2-[(1-methylthio-2-nitroethenyl)amino]ethyl]thio]methyl]-2-furanmethanamine(1.5 g) and 1,3-diaminopropane (0.17 g) at 98°-100° for 2 hours followedby crystallisation from isopropanol.

Found: C,51.0; H,6.7; N,17.7; C₂₇ H₄₄ N₈ O₆ S₂ requires C,50.6; H,6.9;N,17.5%.

(iv)N,N'''-1,3-Propanediylbis-[N"-cyano-N'-[2-[[5-[(dimethylamino)methyl]-2-furanylmethyl]thio]ethyl]guanidine](1 g) as a yellow oil from methylN'-cyano-N-[2-[[5-[(dimethylamino)methyl]-2-furanylmethyl]thio]ethyl]carbaminidothioate (2 g) and 1,3-diaminopropane (0.24 g) at 98°-100° for6 hours followed by column chromatography (silica/methanol).

TLC. (silica/methanol) Rf 0.19.

Found: C,52.9; H,7.2; N,22.5; C₂₇ N₄₂ N₁₀ O₂.1/2H₂ O requires: C,53.0;H,7.1; N,22.9%

(v)N,N"'-1,12-Dodecanediylbis-[N"-cyano-N'-[3-[3-[(dimethylamino)methyl]phenoxy]propyl]guanidine](1.2 g) as yellow oil from methylN'-cyano-N-[3-[3-[(dimethylamino)methyl]phenoxy]propyl]carbamimidothioate(2 g) and 1,12-diaminododecane (0.65 g) at 100° for 6 hours followed bycolumn chromatography (silica/methanol)

TLC. (silica/methanol-0.88 ammonia, 79:1) Rf 0.5

Found: C,65.6; H,9.0; N,19.1; C₄₀ H₆₄ N₁₀ O₂.H₂ O requires: C,65.4;H,9.1; N,19.1%

(vi)N,N-Bis[1-[[3-[3-[(dimethylamino)methyl]phenoxy]propyl]amino]-2-nitroethenyl]-1,4-butanediamine(1.05 g), mp. 146°-148° fromN,N-dimethyl-3-[3-[[1-(methylthio)-2-nitroethenyl]amino]propoxy]benzenemethanamine(1.35 g) and 1,4-diaminobutane (0.183 g) in water (3 ml) and ethanol (3ml) at room temperature for 4 days and crystallisation from ethanol.

Found: C,59.8; H,7.8; N,17.4; C₃₂ H₅₀ N₈ O₆ requires: C,59.8; H,7.8;N,17.4%.

(vii)N,N'-Bis-[1-[[2-[[5-[(dimethylamino)methyl]-2-furanylmethyl]thio]ethyl]amino]-2-nitroethenyl]-1,6-hexanedeiamine(0.54 g) as an amber oil fromN,N-dimethyl-5-[[[2-[(1-methylthio-2-nitroethenyl)amino]ethyl]thio]methyl]-2-furanmethanamine(1 g) and 1,6-hexanediamine in water (5 ml) at 98°-100° for 10 minutesfollowed by column chromatography (silica/methanol-0.88 ammonia, 79:1)

Found: C,50.2; H,7.3; N,15.2; C₃₀ H₅₀ N₈ O₆ S₂.2H₂ O Requires: C,50.1;H,7.6; N,15.6%.

NMR. (CDCl₃)τ: 2.5-3.5(2H,v.br.,2NH), 3.40(2H,s,2CH), 3.82(4H,s,4CH),6.28(4H,s,2CH₂); 6.50(s,2CH₂), 6.20-7.50(br,6CH₂)(16H);7.72(12H,s,4CH₃), 8.00-9.00 (8H,br,4CH₂).

(viii)N,N"'-1,12-Dodecanediylbis[N"-cyano-N'-[2-[[5-[(dimethylamino)methyl]-2-furanylmethyl]thio]ethyl]guanidine](1.45g) as an oil from methylN'-cyano-N-[2-[[5-[(dimethylamino)methyl]-2-furanylmethyl]thio]ethyl]carbamimidothioate(2 g) and 1,12-diaminododecane (0.64 g) at 98°-100° for 3 hours followedby column chromatography (silica/methanol)

TLC. (silica/methanol-0.88 ammonia, 79:1) Rf 0.54

NMR. (CDCl₃)τ: 3.90(4H,AB,4CH), 4.30(2H,t,2NH),4.50(2H,t,2NH),6.35(4H,s,2CH₂); 6.65(s,2CH₂), 6.73(q,2CH₂),6.90(q,2CH₂)(12H); 7.37(4H,t,2CH₂). 7.80(12H,s,4CH₃), 8.8region(20H,m,10CH₂).

EXAMPLE 2

(i)N,N"-1,3-Propanediylbis-[N'-[2-[[5-[(dimethylamino)methyl]-2-furanylmethyl]thio]ethyl]thiourea].

A mixture of5-[[(2-isothiocyanatoethyl)thio]methyl]-N,N-dimethyl-2-furanmethanamine(2.56 g) and 1,3-diaminopropane (0.37 g) in acetonitrile (50 ml) wasstirred at room temperature for 6 hours. The solvent was evaporated invacuo and the residual oil chromatographed (silica/methanol) theappropriate eluate was evaporated in vacuo to give a yellow oil which ontrituration with ether yielded the title compound (1.15 g) as a whitepowder.

TLC. (silica/methanol-0.88 ammonia, 79:1) Rf 0.54.

Found: C,51.0; H,7.2; N,14.1; C₂₅ H₄₂ N₆ O₂ S₄ requires: C,51.2; H,7.2;N,14.3%

Similarly prepared was

(ii)N,N"-1,12-Dodecanediylbis-[N'-[2-[[5-[(dimethylamino)methyl]-2-furanylmethyl]thio]ethyl]thiourea](3.0g) as a white powder from 5-[[(2-isothiocyanatoethyl)thio]methyl]N,N-dimethyl-2-furanmethanamine (2.56 g) and 1,12-diaminododecane (1 g)in acetonitrile (50 ml).

TLC. (silica/methanol-ethyl acetate,2:1) Rf 0.14.

Found: C,57.0; H,8.5; N,11.6; C₃₄ H₆₀ N₆ O₂ S₄ requires: C,57.3; H,8.5;N,11.8%.

EXAMPLE 3N,N"-1,3-Propanediylbis-[N'-[3-[3-[(dimethylamino)methyl]phenoxy]propyl]thiourea]A. 3-(3-Isothiocyanatopropoxy)-N,N-dimethylbenzenemethanamine.

A solution of carbon disulphide (8.36 g) in acetone (16 ml) was addeddropwise to a stirred solution of3-(3-aminopropoxy)-N,N-dimethylbenzenemethanamine (20.8 g) in acetone(60 ml) at -10° to 0° during 15 minutes. A solution of mercuric chloride(27.2 g) in acetone (40 ml) was added slowly at -15° and after theaddition the suspension was warmed to 0° and triethylamine (23 g) addeddropwise. The suspension was refluxed for 45 minutes then filtered andevaporated to give an oil which was chromatographed (alumina,grade3/ether). The appropriate eluate was evaporated to a yellow oilconsisting of the title compound (8.7 g).

TLC. (alumina/ether) Rf 0.44.

NMR. (CDCl₃)τ: 2.77(1H,m,CH), 3.00-3.40(3H,m,3CH), 5.92(2H,t,CH₂),6.26(2H,t,CH₂), 6.62(2H,s,CH₂); 7.77(s,2CH₃), 7.87(m,CH₂)(8H).

B.N,N"-1,3-Propanediylbis-[N'-[3-[3-[(dimethylamino)methyl]phenoxy]propyl]thiourea]A mixture of 3-(3-isothiocyanatopropoxy)-N,N-dimethylbenzenemethanamine(2.24 g) and 1,3-diaminopropane (0.42 g) in acetonitrile (50 ml) wasstirred at room temperature for 24 hours. The solvent was evaporated invacuo and the oily residue chromatographed (silica/methanol) to yieldthe title compound (0.46 g) as a gum.

TLC. (silica/methanol-0.88 ammonia, 79:1) Rf 0.58

Found: C,60.6; H, 8.3; N,14.5; C₂₉ H₄₆ N₆ O₂ S₂ requires: C,60.6; H,8.1;N,14.6%.

EXAMPLE 4

(i)N-[2-[[5-[(Dimethylamino)methyl]-2-furanylmethyl]thio]ethyl]-N'-[12-[[1-(methylamino)-2-nitroethenyl]amino]dodecyl]-2-nitro-1,1-ethenediamine.

A.(i) N-[1-(Methylamino)-2-nitroethenyl]-1,12-dodecanediamine.

A mixture of 1,12-diaminododecane (3 g) andN-methyl-1-(methylthio)-2-nitroethenamine (1.48 g) in water (50 ml) wasstirred at room temperature for 20 hours. The solution was evaporated invacuo and the residue chomatographed (silica/methanol). The appropriateeluate was evaporated to yield the title compound (1.8 g), mp.123°-125°.

Found: C,60.2; H,10.9; N,18.4; C₁₅ H₃₂ N₄ O₂ requires: C,60.0; H,10.7;N,18.6%.

Similarly prepared was:

(ii) N-[1-(Methylamino)-2-nitroethenyl]-1,6-hexanediamine (1 g), mp.113°-115° from 1,6-diaminohexane (1.6 g) andN-methyl-1-(methylthio)-2-nitroethenamine (1.5 g) in water (50 ml) for24 hours followed by column chromatography (silica/methanol).

TLC. (silica/methanol-0.88 ammonia, 79:1) Rf 0.1.

B.(i)N-[2-[[5-[(Dimethylamino)methyl]-2-furanylmethyl]thio]ethyl]-N'-[12-[[1-(methylamino)-2-nitroethenyl)amino]dodecyl]-2-nitro-1,1-ethenediamine.

A mixture ofN,N-dimethyl-5-[[[2-[(1-methylthio-2-nitroethenyl)amino]ethyl]thio]methyl]-2-furanmethanamine(0.8 g) and N-[1-(methylamino)-2-nitroethenyl]-1,12-dodecanediamine (0.8g) was heated at 98°-100° for 4 hours. The oily residue waschromatographed (silica/methanol) and the appropriate eluate evaporatedin vacuo to give a residue which was crystallised from methanol-ethylacetate yielding the title compound (0.85 g), mp. 82°-85°.

Found: C,55.9; H,8.4; N,16.8; C₂₇ H₄₉ N₇ O₅ S requires: C,55.6; H,8.5;N.16.8%.

Similarly prepared was:

(ii)N-[2-[[5-(Dimethylaminomethyl)-2-furanylmethyl]thio]ethyl]-N'-[6-[[1-(methylamino)-2-nitroethenyl]amino]hexyl]-2-nitro-1,1-ethenediamine (1 g), mp. 78°-80° fromN,N-dimethyl-5-[[[2-[(1-methylthio-2-nitroethenyl)amino]ethyl]thio]methyl]-2-furanmethanamine(1.23 g) and N-[1-(methylamino)-2-nitroethenyl]-1,6-hexanediamine (0.8g) in water (25 ml) for 24 hours followed by column chromatography(silica/methanol) and crystallisation from ethyl acetate-ethanol.

Found: C,50.1; H, 7.8; N,19.4; C₂₁ H₃₇ N₇ O₅ S requires: C,50.5; H, 7.5;N.19.6%.

EXAMPLE 5N-[1-[[2-[[5-[(Dimethylamino)methyl]-2-furanylmethyl]thio]ethyl]amino]-2-nitroethenyl]-N'-[[[3-[3-[(1-piperidinyl)methyl]phenoxy]propyl]amino]-2-nitroethenyl]-1,12-dodecanediamine.A.N-[1-[[2-[[5-[(Dimethylamino)methyl]-2-furanylmethyl]thio]ethyl]amino]-2-nitroethenyl]-1,12-dodecanediamine.

A solution ofN,N-dimethyl-[[[2-[(1-methylthio-2-nitroethenyl)amino]ethyl]thio]methyl]-2-furanmethanamine(1.99 g.) and 1,12-dodecyldiamine (4.8 g.) in ethanol (25 ml.) wasstirred at room temperature for 7 days. The solution was evaporated invacuo and the residue chromatographed (silica/methanol-0.880 ammonia,19:1). The appropriate eluate was evaporated to give the title compound(2.2 g.) as a waxy semi-solid.

TLC (silica/methanol-0.880 ammonia, 19:1) R_(F) 0.25

Found: C, 59.9; H, 9.7; N, 14.5; S, 6.2

C₂₄ H₄₅ N₅ O₃ S requires: C, 59.6; H, 9.4; N, 14.5; S, 6.6%

B.2-Nitro-N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-1-(methylthio)etheneamineoxalate.

A mixture of 3-[3-[(1-piperidinyl)methyl]phenoxy]propanamine (4.97 g.)and 1,1-bis-(methylthio)-2-nitroethene (6.61 g.) in tetrahydrofuran (100ml.) was heated under reflux for 19 hours. A solution of oxalic acid(6.25%) in tetrahydrofuran (4 ml.) was added, the suspension filteredand to the filtrate was added a solution of oxalic acid (6.25%) intetrahydrofuran (36 ml.). The solid which separated on trituration wasfiltered, washed with tetrahydrofuran and dried to give the titlecompound (7.36 g.), m.p. 71°-75°.

TLC (silica/methanol-0.880 ammonia, 79:1) R_(F) 0.65

N.M.R. (D₂ O): 2.50(1H, m, CH), 2.70-3.00(3H, m, 3CH); 5.70(s, CH₂),5.75(m, CH₂); 6.25(t, CH₂), 6.48(m, CH₂) (4H); 7.00(2H, m, CH₂),7.45(3H, s, CH₃), 7.50-8.80(8H, m, 4CH₂).

C.2-Nitro-N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-1-(methylthio)ethenamine.

To a solution of2-nitro-N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-1-(methylthio)ethenamineoxalate (0.9 g.) in water (20 ml.) was added sodium bicarbonate (3 g.).The suspension was extracted with ethyl acetate (2×20 ml.), the extractsdried (Na₂ CO₃) and evaporated in vacuo to give the title compound (0.65g.).

TLC (silica/methanol-0.880 ammonia, 79:1) R_(F) 0.65

N.M.R. (CDCl₃): 2.80(1H, m, CH), 3.00-3.30(3H, m, 3CH), 3.40(1H, s, CH),5.90(2H, t, CH₂), 6.40(2H, q, CH₂), 6.50(2H, s, CH₂); 7.55(s, CH₃),7.60(m, 2CH₂), 7.80(m, CH₂) (9H); 8.30-8.70(6H, m, 3CH₂).

D.N-[1-[[2-[[5-[(Dimethylamino)methyl]-2-furanylmethyl]thio]ethyl]amino]-2-nitroethenyl]-N'-[[[3-[3-[(1-piperidinyl)methyl]phenoxy]propyl]amino]-2-nitroethenyl]-1,12-dodecanediamine.

A mixture of2-nitro-N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-1-(methylthio)ethenamine(0.58 g.) andN-[1-[[2-[[5-[(dimethylamino)methyl]-2-furanylmethyl]thio]ethyl]amino]-2-nitroethenyl]-1,12-dodecanediamine(0.77 g.) in methanol (3 ml.) was evaporated and the residue heated at98°-100° for 6 hours. The oily residue was chromatographed(silica/methanol-0.880 ammonia, 79:1) and the appropriate eluateevaporated in vacuo to give the title compound (0.8 g.) as an oil.

TLC (silica/methanol-0.880 ammonia, 79:1) R_(F) 0.5

Found: C, 60.4; H, 8.9; N, 13.5 C₄₁ H₆₈ N₈ O₆ S. H₂ O requires: C, 60.1;H, 8.6; N, 13.7%.

NMR (CDCl₃)τ: -0.32 (2H, m, 2NH), 2.80 (1H, m, CH), 2.80-3.50 (7H, m,2NH and 5 CH), 3.90 (2H, m, 2CH), 5.96 (2H, t, CH₂); 6.31 (s, CH₂),6.40-6.71 (m, 4 CH₂), 6.60 (s, 2CH₂) (14 H); 7.29 (2H, m, CH₂);7.40-8.10 (m, 3CH₂), 7.78 (s, 2CH₃) (12 H); 8.10-9.00 (26 H, m, 13 CH₂).

EXAMPLE 6N-[1-[[2-[[[5-[(Dimethylamino)methyl]-2-furanyl]methyl]thio]ethyl]amino]-2-nitroethenyl]-N'-[1-[[2-[(2-furanylmethyl)thio]ethyl]amino]-2-nitroethenyl]-1,12-dodecanediamine.A. N-2-[[(2-Furanyl)methyl]thio]ethyl-1-(methylthio)-2-nitroethenamine.

A solution of 2-[(2-furanylmethyl)thio]-2-nitroethenamine (3.14 g.) and1,1-bis-(methylthio)-2-nitroethene (13.2 g.) in dioxan (100 ml.) washeated at 100° for 11/2 hours. The solution was evaporated in vacuo andthe residue suspended in warm ethyl acetate (70 ml.). The cooledsuspension was filtered and the filtrate evaporated in vacuo. The oilyresidue was suspended in ether and the solid which separated wasfiltered and crystallised from ethanol to give the title compound (2.17g.), m.p. 68°-70°. TLC (silica/ether-cyclohexane, 4:1) R_(F) 0.3

Found: C, 43.5; H, 5.2; N, 10.1, C₁₀ H₁₄ N₂ O₃ S₂ requires: C, 43.8; H,5.1; N, 10.2%.

B.N-[1-[[2-[[[5-[(Dimethylamino)methyl]-2-furanyl]methyl]thio]ethyl]amino]-2-nitroethenyl]-N'-[1-[[2-[(2-furanylmethyl)thio]ethyl]amino]-2-nitroethenyl]-1,12-dodecanediamine.

A mixture ofN-[1-[[2-[[5-[(dimethylamino)methyl]-2-furanylmethyl]thio]ethyl]amino]-2-nitroethenyl]-1,12-dodecanediamine(0.8 g.) andN-2-[[(2-furanyl)methyl]thio]ethyl-1-(methylthio)-2-nitroethenamine(0.57 g.) in ethyl acetate (8 ml.) was evaporated and the residue heatedat 98°-100° for 2 hours. The oily residue was dissolved in methanol (10ml.) and evaporated to dryness (×2). The oily residue was trituratedwith ethyl acetate (30 ml.), the solid which separated was washed withethyl acetate and dried to give the title compound (0.82 g.), m.p.69°-72°

TLC (silica/methanol) R_(F) 0.35

NMR(CDCl₃)τ: -0.70-0.00 (2H, m, 2NH), 2.70-3.20(2H, m, 2NH), 2.60 (1H,brs, CH), 3.40(2H, brs, 2CH), 3.60-3.90(4H, m, 4CH), 6.28 (4H, brs,2CH₂); 6.30-7.00 (m, 4CH₂), 6.60(s, CH₂)(10H); 7.27 (4H, t, 2CH₂),7.75(6H, s, 2CH₂), 8.10-9.00(20H, m, 10CH₂)

PHARMACEUTICAL COMPOSITIONS

    ______________________________________                                        1.     Tablets                                                                ______________________________________                                        a.     Direct Compression   mg/tablet                                                Active ingredient    200.00                                                   Microcrystalline cellulose BPC                                                                     198.00                                                   Magnesium stearate    2.00                                                    Compression weight   400.00                                            ______________________________________                                    

The active ingredient is sieved through a 250 μm sieve, blended with theexcipients and compressed using 10.0 mm punches. Tablets of otherstrengths may be prepared by altering the compression weight and usingpunches to suit.

    ______________________________________                                        b.    Wet Granulation        mg/tablet                                              Active ingredient      200.00                                                 Lactose B.P.           138.00                                                 Starch B.P.            40.00                                                  Pregelatinised Maize starch B.P.                                                                     20.00                                                  Magnesium Stearate B.P.                                                                              2.00                                                   Compression weight     400.00                                           ______________________________________                                    

The active ingredient is sieved through a 250 μm sieve and blended withthe lactose, starch and pregelatinised starch. The mixed powders aremoistened with purified water, granules are made, dried, screened andblended with the magnesium stearate. The lubricated granules arecompressed into tablets as described for the direct compressionformulae.

The tablets may be film coated with suitable film forming materials,e.g. methyl cellulose or hydroxypropyl methyl cellulose using standardtechniques. Alternatively the tablets may be sugar coated.

    ______________________________________                                        2.     Capsules             mg/capsule                                        ______________________________________                                        Active ingredient       200.00                                                *STA-RX 1500            100.00                                                Magnesium Stearate B.P.  1.50                                                 Fill Weight             300.00 mg.                                            ______________________________________                                         *A form of directly compressible starch supplied by Colorcon Ltd.,            Orpington, Kent.                                                         

The active ingredient is sieved through a 250 μm sieve and blended withthe other materials. The mix is filled into No. 2 hard gelatin capsulesusing a suitable filling machine. Other doses may be prepared byaltering the fill weight and if necessary changing the capsule size tosuit.

    ______________________________________                                        3.     Syrup              mg/5ml dose                                         ______________________________________                                        Active ingredient          200.00                                             Sucrose B.P.              2750.00                                             Glycerine B.P.             500.00                                             Buffer                                                                        Flavor                                                                        Color                     as required                                         Preservative                                                                  Distilled Water             5.00ml                                            ______________________________________                                    

The active ingredient, buffer, flavour, colour and preservative aredissolved in some of the water, and the glycerine is added. Theremainder of the water is heated to 80° C. and the sucrose is dissolvedin this and cooled. The two solutions are combined, adjusted to volumeand mixed. The syrup produced is clarified by filtration.

    ______________________________________                                        4. Injection for Intravenous Administration                                                              % w/v                                              ______________________________________                                        Active ingredient           1.00                                              Water for injection B.P. to                                                                              100.00                                             ______________________________________                                    

Sodium chloride may be added to adjust the tonicity of the solution andthe pH may be adjusted to that of maximum stability and/or to facilitatesolution of the active ingredient using either dilute acid or alkali.

The solution is prepared, clarified and filled into appropriate sizedampoules sealed by fusion of the glass. The injection is sterilised byheating in an autoclave using one of the acceptable cycles.Alternatively the solution may be sterilised by filtration and filledinto sterile ampoules under aseptic conditions. The solution may bepacked under an inert atmosphere of nitrogen.

We claim:
 1. Compounds of the general formula (I) ##STR27## or aphysiologically acceptable salt or hydrate thereof, in which Y and Z,which may be the same or different, each represents oxygen, sulphur,═CHNO₂ or ═NR₃ where R₃ is hydrogen, nitro, cyano, lower alkyl, aryl,alkylsulphonyl or arylsulphonyl;p has a value from 2 to 12; R₁represents ##STR28## in which R₄ and R₅ which may be the same ordifferent each represent hydrogen, lower alkyl, cycloalkyl, loweralkenyl, aralkyl or lower alkyl interrupted by an oxygen atom or a group>N--R₆ in which R₆ represents hydrogen or lower alkyl, or R₄ and R₅together with the nitrogen atom to which they are attached form a 5 to7-membered saturated alkyleneimine ring; Q represents a furan ring inwhich incorporation into the rest of the molecule is through bonds atthe 2 and 5 positions; X represents --CH₂ --, --O-- or --S--; nrepresents zero or 1; m represents 2, 3 or 4 and Alk represents astraight chain alkylene group of 1 to 3 carbon atoms;and R₂ representslower alkyl or the group --(CH₂)_(y) E(CH₂)_(x) G in which Y represents2, 3 or 4 or can additionally represent zero or 1 when E is a --CH₂ --group; x represents zero, 1 or 2; E represents --CH₂ --, --O-- or --S--;and G represents a monocyclic 5 or 6-membered carbocyclic aromatic ring,or a thiophen or furan ring or G represents the group ##STR29## where Q'represents a furan or thiophen ring in which incorporation into the restof the molecule is through bonds at the 2 and 5 positions, or a benzenering in which incorporation into the rest of the molecule is throughbonds at the 1 and 3 or 1 and 4 positions; Alk' represents any of thegroups defined for Alk; and R₄ ' and R₅ ' which may be the same ordifferent represent any of the groups defined for R₄ or R₅.
 2. Compoundaccording to claim 1 in which in the substituent R₁ n is not zero when Xis oxygen and in the substituent R₂ when Q' or G is a furan ring, then xis not zero when E is oxygen.
 3. Compound according to claim 1 in whichR₂ represents ##STR30## where R₄ ', R₅ ', Alk', Q', x and E are asdefined in claim 1 and y is 2, 3 or
 4. 4. Compounds according to claim 1in which R₂ represents an alkyl group.
 5. Compounds according to claim 1in which R₄, R₅, R₄ ' and R₅ ' are alkyl groups.
 6. Compounds accordingto claim 1 in which Alk and/or Alk' is CH₂.
 7. Compounds according toclaim 1 in which m and y are 2 or
 3. 8. Compounds according to claim 1in which p is 3, 4 or
 12. 9. Compounds according to claim 1 in which inthe substituent R₁ n is 1, X is sulphur and m is 2 and in thesubstitutent R₂ Q' is furan, x is 1, E is sulphur and y is
 2. 10.Compounds according to claim 9 in which Y and/or Z is ═CHNO₂ and p is 3or
 12. 11. Compounds according to claim 1 in which Q' is 1,3-benzene, xis zero, E is oxygen and y is
 3. 12. Compounds according to claim 11 inwhich Y and/or Z is ═CHNO₂ or ═S and p is 3 or
 4. 13. Compoundsaccording to claim 1 whichare:N,N'-bis[1-[[5-[(dimethylamino)methyl]-2-furanylmethyl]thio]ethyl]amino]-2-nitroethenyl]-1,3-propanediamineN,N'-bis[1-[[2-[[5-[(dimethylamino)methyl]-2-furanylmethyl]thio]ethyl]amino]-2-nitroethenyl]-1,12-dodecanediamineN-[2-[[5-[(dimethylamino)methyl]-2-furanylmethyl]thio]ethyl]-N'-[12-[[1-(methylamino)-2-nitroethenyl]amino]dodecyl]-2-nitro-1,1-ethenediamine.14. Compounds according to claim 1, in which R₁ and R₂ may be the sameor different and R₁ represents ##STR31## where R₄, R₅, Alk, Q, n, X andm are as defined in formula (I) and R₂ represents ##STR32## where R₄ ',R₅ ', Alk', Q', x and E are as defined in claim 1 and y is 2, 3 or 4with the proviso that n is not zero when X is oxygen and x is not zerowhen E is oxygen and Q' is a furan or thiophen ring system.
 15. Apharmaceutical composition comprising an effective amount of a compoundaccording to claim 1 together with at least one pharmaceuticallyacceptable carrier or diluent, and optionally an effective amount of atleast one other active ingredient.
 16. A pharmaceutical composition asclaimed in claim 15 in which the compound as claimed in claim 1 is inthe form of a physiologically acceptable salt.
 17. A method of treatinga condition mediated through histamine H₂ -receptors which comprisesadministering to a patient an effective amount of a compound as definedin claim 1 to relieve said condition.